Single-stranded regions modulate conformational dynamics and ATPase activity of eIF4A to optimize 5-UTR unwinding
Single-stranded regions modulate conformational dynamics and ATPase activity of eIF4A to optimize 5-UTR unwinding
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DOI：
10.1093/nar/gkz254
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发表时间：
2019-06-04
影响因子：
14.9
通讯作者：
Klostermeier, Dagmar
中科院分区：
文献类型：
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作者：
Andreou, Alexandra Zoi;Harms, Ulf;Klostermeier, Dagmar
真核生物翻译起始需要在mRNA的5-非翻译区解绕二级结构。DEAD-box解旋酶eIF4A被认为与eIF4G和eIF4B一起解开5-UTR中的结构元件。这两个因子通过调节eIF4A在开放和封闭状态之间的构象循环，共同刺激eIF4A的活性。在这里，我们研究RNA底物如何调节eIF4A的活性。rna分为两类：短rna仅部分刺激eIF4A atp酶活性，关闭是构象周期的限速。相比之下，较长的rna最大程度地刺激ATP水解并促进eIF4A的关闭。引人注目的是，解绕的速率常数与双链之前的单链区域的长度无关，但对于具有六个核苷酸的单链区域的RNA达到最大值。我们提出了一个模型，其中RNA底物通过调节eIF4A在无效、非生产性和生产性周期之间的动力学分配来影响eIF4A的活性。
Eukaryotic translation initiation requires unwinding of secondary structures in the 5-untranslated region of mRNA. The DEAD-box helicase eIF4A is thought to unwind structural elements in the 5-UTR in conjunction with eIF4G and eIF4B. Both factors jointly stimulate eIF4A activities by modulation of eIF4A conformational cycling between open and closed states. Here we examine how RNA substrates modulate eIF4A activities. The RNAs fall into two classes: Short RNAs only partially stimulate the eIF4A ATPase activity, and closing is rate-limiting for the conformational cycle. By contrast, longer RNAs maximally stimulate ATP hydrolysis and promote closing of eIF4A. Strikingly, the rate constants of unwinding do not correlate with the length of a single-stranded region preceding a duplex, but reach a maximum for RNA with a single-stranded region of six nucleotides. We propose a model in which RNA substrates affect eIF4A activities by modulating the kinetic partitioning of eIF4A between futile, unproductive, and productive cycles.